The human immunodeficiency virus HIV is the causative agent of acquired immunodeficiency syndrome (AIDS), a disease characterized by the destruction of the immune system, particularly of the CD4+ T-cell, with attendant susceptibility to opportunistic infections. HIV infection is also associated with a precursor AIDS—related complex (ARC), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss.
In common with other retroviruses, the HIV genome encodes protein precursors known as gag and gag-pol which are processed by the viral protease to afford the protease, reverse transcriptase (RT), endonuclease/integrase and mature structural proteins of the virus core. Interruption of this processing prevents the production of normally infectious virus. Considerable efforts have been directed towards the control of HIV by inhibition of virally encoded enzymes.
Currently available chemotherapy targets two crucial viral enzymes: HIV protease and HW reverse transcriptase. (J. S. G. Montaner et al. Antiretroviral therapy: “the state of the art”, Biomed & Pharmacother. 1999 53:63-72; R. W. Shafer and D. A. Vuitton, Highly active retroviral therapy (HAART) for the treatment of infection with human immunodeficiency virus type 1, Biomed. & Pharmacother. 1999 53:73-86; E. De Clercq, New Developments in Anti-HIV Chemotherapy. Curr. Med. Chem. 2001 8:1543-1572). Two general classes of RTI inhibitors have been identified: nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI).
NRTIs typically are 2′,3′-dideoxynucleoside (ddN) analogs which must be phosphorylated prior to interacting with viral RT. The corresponding triphosphates function as competitive inhibitors or alternative substrates for viral RT. After incorporation into nucleic acids the nucleoside analogs terminate the chain elongation process. HIV reverse transcriptase has DNA editing capabilities which enable resistant strains to overcome the blockade by cleaving the nucleoside analog and continuing the elongation. Currently clinically used NRTIs include zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC) and tenofovir (PMPA).
NNRTIs were first discovered in 1989. NNRTI are allosteric inhibitors which bind reversibly at a nonsubstrate binding site on the HIV reverse transcriptase thereby altering the shape of the active site or blocking polymerase activity. (R. W. Buckheit, Jr., Non-nucleoside reverse transcriptase inhibitors: perspectives for novel therapeutic compounds and strategies for treatment of HIV infection, Expert Opin. Investig. Drugs 2001 10(8)1423-1442; E. De Clercq The role of non0-nuceloside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection, Antiviral Res. 1998 38:153-179; G. Moyle, The Emerging Roles of Non-Nucleoside Reverse Transcriptase Inhibitors in Antiviral Therapy, Drugs 2001 61(1):19-26) Although over thirty structural classes of NNRTIs have been identified in the laboratory, only three compounds have been approved for HIV therapy: efavirenz, nevirapine and delavirdine. Although initially viewed as a promising class of compounds, in vitro and in vivo studies quickly revealed the NNRTIs presented a low barrier to the emergence of drug resistant HIV strains and class-specific toxicity. Drug resistance frequently develops with only a single point mutation in the RT.
While combination therapy with NRTIs, PIs and NNRTIs has, in many cases, dramatically lowered viral loads and slowed disease progression, significant therapeutic problems remain. The cocktails are not effective in all patients, potentially severe adverse reactions often occur and the rapidly-replicating HIV virus has proven adroit at creating mutant drug-resistant variants of wild type protease and reverse transcriptase.
There remains a need for safer drugs with activity against wild type and commonly occurring resistant strains of HIV. Benzyl-pyridazinone compounds have been extensively investigated as thyroxin analogs which can decrease plasma cholesterol without stimulating cardiac activity (A. H. Underwood et al. A thyromimetic that decreases plasma cholesterol without increasing cardiovascular activity Nature 1986 324(6096):425429; P. D. Leeson et al. Selective thyromimetics. Cardiac-sparing thyroid hormone analogs containing 3′-arylmethyl substituents J. Med Chem 1989 32(2):320-326; P. D. Leeson et al. EP 0188351). WO9624343 (D. J. Dunnington) discloses oxo-pyridazinylmethyl substituted tyrosines are selective antagonists for the haematopoietic phosphatase SH2 domain which may render them useful to increase erythropoiesis and haematopoiesis. WO 9702023 (D. J. Dunnington) and WO9702024 (D. J. Dunnington) further disclose these compounds are specific inhibitors of the human Stat 6 SH2 domain and may be useful for treating asthma, allergic rhinitis and anemia. WO2001085670 (H. Shiohara et al.) discloses related malonamide derivatives useful for treating circulatory diseases. EP 810218 (D. A. Allen et al.) discloses benzoyl substituted benzyl-pyridazinone compounds which are cyclooxygenase inhibitors and potential antiinflammatory or analgesic compounds. None of the references teaches therapy for HIV infections or inhibition of HIV reverse transcriptase.